Faculty, Staff and Student Publications
Publication Date
12-12-2023
Journal
Cancer Discovery
Abstract
Oncogenic KRAS (KRAS*) contributes to many cancer hallmarks. In colorectal cancer, KRAS* suppresses antitumor immunity to promote tumor invasion and metastasis. Here, we uncovered that KRAS* transforms the phenotype of carcinoma-associated fibroblasts (CAF) into lipid-laden CAFs, promoting angiogenesis and tumor progression. Mechanistically, KRAS* activates the transcription factor CP2 (TFCP2) that upregulates the expression of the proadipogenic factors BMP4 and WNT5B, triggering the transformation of CAFs into lipid-rich CAFs. These lipid-rich CAFs, in turn, produce VEGFA to spur angiogenesis. In KRAS*-driven colorectal cancer mouse models, genetic or pharmacologic neutralization of TFCP2 reduced lipid-rich CAFs, lessened tumor angiogenesis, and improved overall survival. Correspondingly, in human colorectal cancer, lipid-rich CAF and TFCP2 signatures correlate with worse prognosis. This work unveils a new role for KRAS* in transforming CAFs, driving tumor angiogenesis and disease progression, providing an actionable therapeutic intervention for KRAS*-driven colorectal cancer.
Keywords
Animals, Humans, Mice, Angiogenesis, Cancer-Associated Fibroblasts, Colonic Neoplasms, Colorectal Neoplasms, DNA-Binding Proteins, Fibroblasts, Lipids, Proto-Oncogene Proteins p21(ras), Transcription Factors, Tumor Microenvironment
DOI
10.1158/2159-8290.CD-22-1467
PMID
37768068
PMCID
PMC10807546
PubMedCentral® Posted Date
June 2024
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Included in
Bioinformatics Commons, Biomedical Informatics Commons, Digestive System Diseases Commons, Gastroenterology Commons, Medical Sciences Commons, Oncology Commons